This invention relates to compounds useful as antiretroviral agents. More particularly, this invention relates to pyridine and quinoline derivatives which inhibit replication of the retroviruses HIV-1, HIV-2 and human cytomegalovirus (HCMV).
There are currently about seven nucleoside reverse transcriptase (RT) inhibitors (NRTIs), about three nonnucleoside RT inhibitors (NNRTI) and about six protease inhibitors (PI) officially approved for the treatment of HIV-infected individuals. Reverse transcriptase and protease are virus-encoded enzymes. The clinical efficacy of the individual drugs varies depending on the nature and the molecular target of the drugs.
U.S. Pat. No. 5,268,389 describes certain thiocarboxylate ester compounds that are said to inhibit replication of HIV. It is alleged that the selectivity of these compounds for HIV-1 is due to a highly specific interaction with HIV-1 RT.
U.S. Pat. No. 5,696,151 is directed to certain carbothioamides that inhibit replication of HIV-1 and reverse transcriptase mutants thereof.
The rapid emergence of HIV-1 strains resistant to several HIV-1 -specific RT inhibitors in cell culture and in AIDS patients has caused concern for further development of these inhibitors in the clinic. See, e.g., Balzarini et al, J. Virology 67(9): 5353-5359 (1993) (xe2x80x9cBalzarini Ixe2x80x9d) and Balzarini et al, Virology 192: 246-253 (1993) (xe2x80x9cBalzarini IIxe2x80x9d).
Failure of long-term efficacy of known drugs can be associated with the appearance of dose-limiting and/or long-term side-effects, or more importantly, with the emergence of drug-resistant virus strains. Both RT inhibitors and protease inhibitors tend to select for virus strains that show a reduced susceptibility for the particular drugs. Moreover, a considerable cross-resistance exists between drugs that act against the same target.
Attempts have been made to combine various HIV-1 RT inhibitors to eliminate virus resistance. See, e.g., Balzarini I, supra. However, there is still a need for new compounds for the treatment of HIV that act at a target (either viral or cellular) that is different from those at which the existing drugs act.
It is the purpose of this invention to provide compounds which, by themselves, can inhibit or suppress the emergence of HIV-1, HIV-2 and HCMV.
This invention relates to the novel compounds 2-[[1-(5-amino-2-methylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 1],1,4-xylyl-bis-2-sulfonyl pyridine-N-oxide [compound 23], 1,4[1,2,4,5-tetramethylbenzyl]-bis-(2xe2x80x2-sulfonylpyridine-N-oxide) [compound 25], 2-(4xe2x80x2-tert-pentylphenylmethylsulfonyl)pyridine-N-oxide [compound 40], 2[1-(9-anthryl)methylsulfonyl]pyridine-N-oxide [compound 51], ethyl-N-[4-(pyridyl-N-oxide-2-sulfonylmethyl)phenylcarbonyl]carbamate [compound 60], 2-[(3-methoxy-4-benzyloxy)phenylmethylsulfonyl]pyridine-N-oxide [compound 61], 2-[[(2-nitro-5-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 62], 2-[[[2,5-bis(1-methylethyl)-4-bromophenyl]methyl]sulfonyl]pyridine-N-oxide [compound 63], 2-[[(3-nitro4-chlorophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 64], 2-[[(3,5-dinitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 65], 2-[[(3-methyl-4-nitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 66], 2-[[(3-nitro-4-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 67], 2-[[(2-chloro-4-nitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 69], 2-[(2,5-dimethylphenyl)chloromethylsulfonyl]-6-methylpyridine-N-oxide [compound73], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]-6-chloropyridine-N-oxide [compound 76], 2-(2,5-dimethylphenylmethylsulfonyl)-6-chloropyridine-N-oxide [compound 77], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]-4,6-dimethylpyridine-N-oxide [compound 81], 2[(2,5-dimethylphenyl)chloromethylsulfonyl]pyridine [compound 106], 8-ethyl-4-methyl-2-[(1-phenylethyl)sulfonyl]quinoline [compound 107], 2-[[1 -(2,5-dimethylphenyl)-2-methoxyethyl]sulfonyl]pyridine [compound 123], 3-chloro-2-[[1-(2,5-dimethylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 124], 3-chloro-2-[[chloro-(2,5-dimethylpbenyl)methyl]sulfonyl]pyridine-N-oxide [compound 125], 3-chloro-2-[(phenylmethyl)thio]pyridine-N-oxide [compound 132], 3-chloro-2-[[(2,5-dimethylphenyl)methyl]thio]pyridine-N-oxide [compound 133], 4-(1,1 -dimethylethyl)-2-[(4-methoxyphenyl)methylthio]pyridine-N-oxide [compound 134], 3-chloro-2-[(phenylmethyl)sulfinyl]pyridine-N-oxide [compound 136], 2-[[(2,6-dichlorophenyl)methyl]thio]-3-methyl-pyridine-N-oxide [compound 137], 2-[[(2,6-dichlorophenyl)methyl]sulfinyl]-3-methyl-pyridine-N-oxide [compound 138], 2-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-methyl-pyridine-N-oxide [compound 139], 2[[(2,5-dimethylphenyl)methyl]thio]-1-methylpyridinium chloride [compound 142], 2-benzylthio-3-nitropyridine [compound 146], 2-((2,5-dimethylphenyl)methylthio) pyridine [compound 148], 6-chloro-(2-benzylthio)pyridine-N-oxide [compound 149], 2-(2,5-dimethylbenzylsulfonyl)pyridine [compound 150], 5-chloro-2(benzylthio) pyridine-N-oxide [compound 151], 2-(N-methyl-3-piperidylmethylthio)pyridine-N-oxide [compound 156], 2-(2,5-dimethylphenylmethylthio)pyridine hydrochloride [compound 157], 2-(1-cyano-2-phenylethenethio) pyridine-N-oxide [compound 158], 2-[1-cyano-2-(p-methoxyphenyl)ethenethio]pyridine-N-oxide [compound 159], 2-[1-cyano-2-(3,4,5-trimethoxyphenyl)ethenethio]pyridine-N-oxide [compound 160], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]pyridine [compound 161], 2-[[1-(2,5-dimethylphenyl)ethyl]thio]-4-methylquinoline [compound 162] and 2-(2,5-dimethylphenyl)methylsulfinyl)pyridine [compound 163], and pharmaceutically acceptable salts thereof
The compounds of this invention are useful for inhibiting replication of HIV-1, HIV-2 and HCMV in vitro and in vivo. The compounds are also useful in the therapeutic or prophylactic treatment of diseases caused by these viruses.
This invention additionally relates to pharmaceutical compositions containing one or more of the above recited compounds and a pharmaceutically acceptable carrier.
This invention relates to the following novel compounds: 2-[[1-(5-amino-2-methylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 1], 1,4-xylyl-bis-2-sulfonyl pyridine-N-oxide [compound 23], 1,4[1,2,4,5-tetramethylbenzyl]-bis-(2xe2x80x2-sulfonylpyridine-N-oxide) [compound 25], 2-(4xe2x80x2-tert-pentylphenylmethylsulfonyl)pyridine-N-oxide [compound 40], 2[1-(9-anthryl)methylsulfonyl]pyridine-N-oxide [compound 51], ethyl-N-[4-(pyridyl-N-oxide-2-sulfonylmethyl)phenylcarbonyl]carbamate [compound 60], 2-[(3-methoxy-4-benzyloxy)phenylmethylsulfonyl]pyridine-N-oxide [compound 61], 2-[[(2-nitro-5-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 62], 2-[[[2,5-bis(1-methylethyl)4-bromophenyl]methyl]sulfonyl]pyridine-N-oxide [compound 63], 2-[[(3-nitro-4-chlorophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 64], 2-[[(3,5-dinitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 65], 2-[[(3-methyl-4-nitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 66], 2-[[(3-nitro-4-methylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 67], 2-[[(2-chloro-4-nitrophenyl)methyl]sulfonyl]pyridine-N-oxide [compound 69], 2-[(2,5-dimethylphenyl)chloromethylsulfonyl]-6-methylpyridine-N-oxide [compound73], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]-6-chloropyridine-N-oxide [compound 76], 2-(2,5-dimethylphenylmethylsulfonyl)-6-chloropyridine-N-oxide [compound 77], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]-4,6-dimethylpyridine-N-oxide [compound 81], 2[(2,5-dimethylphenyl)chloromethylsulfonyl]pyridine [compound 106], 8-ethyl-4-methyl-2-[(1-phenylethyl)sulfonyl]quinoline [compound 107], 2-[[1-(2,5-dimethylphenyl)-2-methoxyethyl]sulfonyl]pyridine [compound 123], 3-chloro-2-[[1-(2,5-dimethylphenyl)ethyl]sulfonyl]pyridine-N-oxide [compound 124], 3-chloro-2-[[chloro-(2,5-dimethylphenyl)methyl]sulfonyl]pyridine-N-oxide [compound 125], 3-chloro-2-[(phenylmethyl)thio]pyridine-N-oxide [compound 132], 3-chloro-2-[[(2,5-dimethylphenyl)methyl]thio]pyridine-N-oxide [compound 133], 4-(1,1-dimethylethyl)-2-[(4-methoxyphenyl)methylthio]pyridine-N-oxide [compound 134], 3-chloro-2-[(phenylmethyl)sulfinyl]pyridine-N-oxide [compound 136], 2-[[(2,6-dichlorophenyl)methyl]thio]-3-methyl-pyridine-N-oxide [compound 1371, 2-[[(2,6-dichlorophenyl)methyl]sufionyl]-3-methyl-pyridine-N-oxide [compound 138], 2-[[(2,6-dichlorophenyl)methyl]sulfonyl]-3-methyl-pyridine-N-oxide [compound 139], 2[[(2,5-dimethylphenyl)methyl]thio]-1-methylpyridinium chloride [compound 142], 2-benzylthio-3-nitropyridine [compound 146], 2-((2,5-dimethylphenyl) methylthio)pyridine [compound 148], 6-chloro-(2-benzylthio)pyridine-N-oxide [compound 149], 2-(2,5-dimethylbenzylsulfonyl) pyridine [compound 150], 5-chloro-2(benzylthio)pyridine-N-oxide [compound 151], 2-(N-methyl]-3-piperidylmethylthio)pyridine-N-oxide [compound 156], 2-(2,5-dimethylphenylmethylthio)pyridine hydrochloride [compound 157], 2-(1-cyano-2-phenylethenethio) pyridine-N-oxide [compound 158], 2-[1-cyano-2-(p-methoxyphenyl)ethenethio]pyridine-N-oxide [compound 159], 2-[1-cyano-2-(3,4,5-trimethoxyphenyl)ethenethio]pyridine-N-oxide [compound 160], 2-[1-(2,5-dimethylphenyl)ethylsulfonyl]pyridine [compound 161], 2-[[1-(2,5-dimethylphenyl)ethyl]thio]-4-methylquinoline [compound 162] and 2-(2,5-dimethylphenyl)methylsulfinyl)pyridine [compound 163] and pharmaceutically acceptable salts thereof.
It will be apparent to those of skill in the art that certain compounds herein may have at least one asymmetrical carbon atom and therefore all isomers, including diastereomers and rotational isomers of such compounds are contemplated as being part of this invention. The invention includes (+)- and (xe2x88x92)-isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound herein. Those skilled in the art will appreciate that for some compounds herein, one isomer may show greater pharmacological activity than other isomers.
It will also be apparent to those of skill in the art that certain compounds herein can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
It will also be apparent to those of skill in the art that certain compounds herein with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
It will also be apparent to those of skill in the art that certain compounds herein may be acidic (e.g., compounds containing a carboxyl group). Acidic compounds according to the present invention can form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, lithium, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine, and the like.
Compounds such as those disclosed herein may be prepared by a variety of methods known to those skilled in the art. For example, U.S. Pat. Nos. 3,960,542, 4,019,893, 4,050,921, and 4,294,970 the contents of each being incorporated herein by reference, describe methods of preparing 2-thio-, 2-sulfinyl-, and/or 2-sulfonyl-pyridine N-oxide derivatives. For example, the parent 2-thiopyridine N-oxides may be prepared, e.g., by two procedures: (1) the reaction of 2-chloropyridine N-oxide with the appropriate mercaptan in the presence of an acid acceptor such as an alkaline earth hydroxide; (2) reaction of the sodium salt of 2-mercaptopyridine N-oxide with a suitable halide preferably of, but not limited to, the benzyl type. The yields of the two procedures are comparable.
The aryl (or heteroaryl) alkylthiopyridines produced above may be oxidized by methods well known to those skilled in the art. The oxidation involves the conversion of both the sulfur and nitrogen to their higher oxidative states in a single preparative step. In this case the products are sulfones as the sequence of oxidation proceeds from sulfidexe2x86x92sulfoxidexe2x86x92sulfonexe2x86x92sulfone N-oxide. The oxidant most generally employed, but not limited to, is 30-50% hydrogen peroxide in glacial acetic acid. In excess of three equivalents of peroxide is necessary. The conversion of the aryl (or heteroaryl) alkylthiopyridine-N-oxides to analogous sulfinyl or sulfonyl compound may be accomplished by employing one or two equivalents of an oxidizing agent selected from, but not necessarily limited to, hydrogen peroxide, peracetic acid, and the aromatic peroxy acids. The ratio of peroxide to substrate varies with the desired product.
The solvents employed may vary with the oxidant as described in the literature (Katritsky and Lagowski, Chemistry of the Heterocyclic N-Oxides, Academic Press, 1971). Glacial acetic acid and water are preferred when hydrogen peroxide is used and a nonpolar solvent such as chloroform is preferred for use with the aromatic peroxy acids. When water is employed as a solvent, a catalyst of the nature of a tungsten, vanadium, zirconium or molybdenum salt (U.S. Pats. Nos. 3,005,852, 3,006,962, and 3,006,963 and British Pat. No. 1,335,626; the contents of each being incorporated by reference herein) is generally used. Temperature and time are a function of the sulfide employed with the range varying from about 50xc2x0 C. to reflux in the case of water and acetic acid to about 0xc2x0 to about 60xc2x0 C. with chloroform.
The synthesis of 2-(alpha-aryl-alpha-chloromethyl sulfonyl) pyridine-N-oxides is also known and described in U.S. Pat. No. 4,360,677 the contents of which are incorporated by reference herein. The types of starting materials generally employed in the preparation of these compounds arc known to those skilled in the art. These parent 2-aryl methylsulfonylpyridine-N-oxides may be prepared by methods described in U.S. Pat. No. 3,960,542. Their subsequent conversion to (alphachloromethylsulfonyl)pyridine-N-oxides may be carried out using a modification of a known procedure. (C. Y. Meyers, et al., J. Org. Chem., 91,7510 (1969); C. Y. Meyers, et al., Tetrahedron Lett., 1105 (1974); the contents of each being incorporated by reference herein).
The solvent, N,N-dimethylformamide, is used without drying. Sodium hydroxide (97 -98%) is freshly ground to a powder before use, care being taken to avoid prolonged exposure to moisture. Temperature may generally be maintained from about xe2x88x925xc2x0 to about +5xc2x0 C., with reaction times between about 25 and about 35 min.
The synthesis of substituted pyridine N-oxide compounds is described in U.S. Pat. No. 4,394,155 and foreign patent publication EP 36388 the contents of each being incorporated by reference herein. The substituted pyridine N-oxide compounds are generally prepared, e.g., by first preparing the appropriate thio compound. An essentially equimolar amount of an alkali metal alkoxide is added with stirring at room temperature under an atmosphere of nitrogen to the substituted or non-substituted benzylmercaptan dissolved in a suitable solvent (such as a C1 to C4 aliphatic alcohol, preferably methanol). The resulting solution is added slowly to a solution of a substituted pyridine N-oxide hydrochloride, which has been treated with an essentially equimolar amount of alkali metal alkoxide. The molar ratio of mercaptide anion to pyridine N-oxide is maintained at about 1, and stirring, nitrogen atmosphere and reaction at room temperature are also maintained throughout the complete reaction. After all the reactants have been combined, the reaction mixture is refluxed from about one to about six hours. The thio product which precipitates when the reaction mixture is poured into a large excess of ice water is filtered, washed several times with water, air dried and recrystallized from an alcohol such as wet ethanol.
The thio compound may be oxidized to the desired sulfinyl or sulfonyl compound by known means, e.g. the thio compound dissolved in excess chloroform is stirred into a chloroform solution of m-chloroperbenzoic acid at about xe2x88x9210xc2x0 to about 10xc2x0 C. The reaction vessel is stoppered and kept at about 0xc2x0 C. for about 24 hr. The by-product, m-chlorobenzoic acid, is removed by filtration and the remaining chloroform solution washed thoroughly with aqueous sodium bicarbonate solution, then water. The chloroform solution is dried (e.g. with anhydrous magnesium sulfate) and the solvent evaporated. The final product may be recrystallized from a suitable solvent (e.g. lower alcohol).
The compounds of the present invention can be administered in any conventional dosage form known to those skilled in the art. Pharmaceutical compositions containing the compounds herein can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. All routes of administration are contemplated including, but not limited to, parenteral, transdermal, subcutaneous, intramuscular, sublingual, inhalation, rectal and topical.
Thus, appropriate unit forms of administration include oral forms such as tablets, capsules, powders, cachets, granules and solutions or suspensions, sublingual and buccal forms of administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal, intraoccular or rectal forms of administration.
When a solid composition is prepared in the form of tablets, e.g., a wetting agent such as sodium lauryl sulfate can be added to micronized or non-micronized compounds herein and mixed with a pharmaceutical vehicle such as silica, gelatine starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, various polymers, or other appropriate substances. Tablets can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously or at predetermined intervals, e.g., by using ionic resins and the like.
A preparation in the form of gelatin capsules may be obtained, e.g., by mixing the active principle with a diluent, such as a glycol or a glycerol ester, and incorporating the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir can contain the active principle together, e.g., with a sweetener, methylparaben and propylparaben as antiseptics, flavoring agents and an appropriate color.
Water-dispersible powders or granules can contain the active principle mixed, e.g., with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners and/or other flavoring agents.
Rectal administration may be provided by using suppositories which may be prepared, e.g., with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
Parenteral, intranasal or intraocular administration may be provided by using, e.g., aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and/or solubilizers, for example, propylene glycol or polyethylene glycol.
Thus, to prepare an aqueous solution for intravenous injection, it is possible to use a co-solvent, e.g., an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween(copyright) 80. An oily solution injectable intramuscularly can be prepared, e.g., by solubilizing the active principle with a triglyceride or a glycerol ester.
Topical administration can be provided by using, e.g., creams, ointments or gels.
Transdermal administration can be provided by using patches in the form of a multilaminate, or with a reservoir, containing the active principle and an appropriate solvent.
Administration by inhalation can be provided by using, e.g., an aerosol containing sorbitan trioleate or oleic acid, for example, together with trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system containing the active principle, by itself or associated with an excipient, in powder form.
The active principle can also be formulated as microcapsules or microspheres, e.g., liposomes, optionally with one or more carriers or additives.
Implants are among the prolonged release forms which can be used in the case of chronic treatments. They can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
The daily dose of a compound as described herein for treatment of a disease or condition cited above is about 0.001 to about 100 mg/kg of body weight per day, preferably about 0.001 to about 10 mg/kg. For an average body weight of 70 kg, the dosage level is therefore from about 0.1 to about 700 mg of drug per day, given in a single dose or 2-4 divided doses. It is contemplated that any range of the aforementioned doses may be administered at intervals greater than daily, e.g., one of four times per week over a period of several weeks or for greater periods. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.
The therapeutically effective amount of the compounds of this invention that can be combined with the pharmaceutically acceptable carrier to produce a single dosage form will vary depending upon the age and condition of the host treated and the particular mode of administration. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford antiretrovirally effective results without causing any medically unacceptable harmful or deleterious side effects.
While the compounds of this invention can be administered as the sole active pharmaceutical agents, the compounds can also be used in combination with one or more other pharmaceutical agents which are not deleterious to the activity of the compounds of this invention or whose combination with the compounds will not have a deleterious effect on the host treated. Indeed, it is also contemplated that compounds of this invention may be combined with other antiviral agents or other agents useful in the treatment of conditions resulting from viral infection.
The following examples are provided to merely illustrate certain aspects of the present invention and should not be construed as a limitation thereof.